Cigarette smoking is the leading preventable cause of morbidity and mortality in the U.S. About 23% of adolescents are regular smokers. To further reduce adolescent smoking, factors that protect against adolescent smoking need to be identified and subsequently incorporated into youth smoking prevention programs. Physical activity may be an important protective factor against youth smoking initiation and progression. Although longitudinal studies of smoking and physical activity indicate that higher levels of physical activity reduce the odds of adolescent smoking initiation and progression, the nature of this relationship, the mechanisms explaining this protective relationship, the amount of physical activity needed to confer a protective effect, and the adolescents at risk for smoking due to their levels of physical activity remain unclear. We propose to address this gap by creating a cohort of 1,000 adolescents (age 14 years) and following them over a four-year period (age 18 years). Socio-environmental, behavioral and psychological influences on smoking and physical inactivity will be collected. The aims of the proposed study are to (1) clarify the nature of the relationship between smoking and physical activity, (2) evaluate the mechanisms explaining the physical inactivity and smoking relationship, (3) empirically identify distinct longitudinal paths or smoking-physical inactivity trajectories to determine optimal intervention timing and the amount of physical activity needed to protect against smoking, and (4) characterize these trajectories by socio-environmental, behavioral and psychological variables to identify adolescents at risk for smoking within the context of their physical activity habits. Specific outcomes of interest include (a) odds and rates of progression to regular smoking and physical inactivity, and (b) longitudinal patterns or smoking-physical inactivity trajectories. This will be one of the first studies to concurrently and comprehensively evaluate smoking and physical activity from mid to late adolescence, to elucidate and quantify the protective relationship, and to explore how theory-based mechanisms relate to critical points in the development of a smoking habit often carried into adulthood. Results from this study can be used to inform the timing, type, amount of physical activity, target variables and important subpopulations for adolescent smoking prevention and intervention programs. Smoking and physical inactivity are two health risk behaviors often formed in adolescence and carried into adulthood. Although, the available longitudinal studies of smoking and physical activity indicate that higher levels of physical activity reduce the odds of adolescent smoking initiation and progression by 50%, the nature of this relationship, why physical activity is protective, and the amount of physical activity needed to confer a protective effect are unclear. This information is critical to for determining the content, timing, and targets for youth smoking prevention intervention that incorporates a physical activity component.